This application requests support for a 4 year, 4 site randomized sham-controlled trial of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depression. TMS has shown an antidepressant effect in 20 small sample randomized controlled comparisons, five separate meta-analyses of these studies, and in randomized trials with electroconvulsive therapy. However, the sample sizes of these studies have been small and the TMS stimulus administered may not have been optimal for antidepressant effect. Considerable skepticism and many questions remain concerning the ultimate clinical meaningfulness of these studies. Recent scientific evidence and pilot data from our groups support the fact that the antidepressant response to rTMS is dose-dependent. The present protocol uses TMS parameters that maximize the stimulation duration and intensity within the published safety guidelines to treat 240 unipolar depressed adults with moderate levels of treatment resistance. We will investigate the safety and efficacy of repeated daily left prefrontal TMS at 120% of motor threshold (MT) in a 3 week fixed dose trial. In subjects showing an antidepressant response after 3 weeks, rTMS will be administered for up to 6 weeks to achieve remission of clinical symptoms of depression. Patients who do not remit with the initial fixed dose trial will be administered rTMS in an open dose escalation trial with the intensity of rTMS increased to a maximum of 140% MT. Baseline magnetic resonance images will be used to determine the optimal stimulus intensity by adjusting for individual variations in cortical to skull distances. Safety measures will include the most comprehensive neuropsychological testing and adverse event profile used to date. We will also determine the long-term antidepressant affect of TMS in remitters, using a standardized continuation medication protocol over 6 months. Finally, we will evaluate whether neuroanatomic findings on magnetic resonance image, stimulus location, demographic, and/or clinical variables affect clinical response to TMS. (This coordinating Center Grant (CCG) application is submitted under a CSMD mechanism, linked to 4 clinical site grants (CSG).